Modulation of resting-state functional connectivity in default mode network is associated with the long-term treatment outcome in major depressive disorder.

BACKGROUND: Treatment non-response and recurrence are the main sources of disease burden in major depressive disorder (MDD). However, little is known about its neurobiological mechanism concerning the brain network changes accompanying pharmacotherapy. The present study investigated the changes in the intrinsic brain networks during 6-month antidepressant treatment phase associated with the treatment response and recurrence in MDD. METHODS: Resting-state functional magnetic resonance imaging was acquired from untreated patients with MDD and healthy controls at baseline. The patients' depressive symptoms were monitored by using the Hamilton Rating Scale for Depression (HAMD). After 6 months of antidepressant treatment, patients were re-scanned and followed up every 6 months over 2 years. Traditional statistical analysis as well as machine learning approaches were conducted to investigate the longitudinal changes in macro-scale resting-state functional network connectivity (rsFNC) strength and micro-scale resting-state functional connectivity (rsFC) associated with long-term treatment outcome in MDD. RESULTS: Repeated measures of the general linear model demonstrated a significant difference in the default mode network (DMN) rsFNC change before and after the 6-month antidepressant treatment between remitters and non-remitters. The difference in the rsFNC change over the 6-month antidepressant treatment between recurring and stable MDD was also specific to DMN. Machine learning analysis results revealed that only the DMN rsFC change successfully distinguished non-remitters from the remitters at 6 months and recurring from stable MDD during the 2-year follow-up. CONCLUSION: Our findings demonstrated that the intrinsic DMN connectivity could be a unique and important target for treatment and recurrence prevention in MDD.

The association of potentially inappropriate medications, polypharmacy and anticholinergic burden with readmission and emergency room revisit after discharge: A hospital-based retrospective cohort study.

AIMS: While certain drug-use indicators are known to be associated with clinical outcomes, the relationship is unclear for some highly prevalent conditions in in patients aged ≥65 years. We examine correlations between 3 drug-use indicators and postdischarge healthcare services use by older patients according to the presence of dementia, advanced age and frailty. METHODS: This retrospective cohort study analysed data collected from hospital electronic health records between April and December 2017. Potentially inappropriate medications (PIMs) and anticholinergic burden were assessed using the 2015 Beers Criteria and anticholinergic cognitive burden scale (ACBS) score. Minor and major polypharmacy were defined as the use of 5-9 and ≥10 drugs, respectively. Outcomes were set as emergency room revisits and readmissions at 1, 3 and 6 months postdischarge. The correlation between drug-use indicators and outcomes was analysed by multivariable logistic regression. RESULTS: The final cohort included 3061 patients for the analysis, and 2930, 2671 and 2560 patients were followed up to 1, 3 and 6 months after discharge. After controlling for confounders, all 3 drug-use indicators were significantly associated with readmission and emergency room revisits except for the relationship between PIMs and readmission within 6 months. These associations were significantly observed among patients without dementia, aged >80 years and with frailty. CONCLUSION: PIMs, polypharmacy and anticholinergic burden are common at discharge and correlate with future use of healthcare services. In older patients, the absence of dementia, advanced age and frailty should be given extra consideration with regard to medication safety.

AuAg nanocomposites suppress biofilm-induced inflammation in human osteoblasts.

Staphylococcus aureus (S. aureus)forms biofilm that causes periprosthetic joint infections and osteomyelitis (OM) which are the intractable health problems in clinics. The silver-containing nanoparticles (AgNPs) are antibacterial nanomaterials with less cytotoxicity than the classic Ag compounds. Likewise, gold nanoparticles (AuNPs) have also been demonstrated as excellent nanomaterials for medical applications. Previous studies have showed that both AgNPs and AuNPs have anti-microbial or anti-inflammatory properties. We have developed a novel green chemistry that could generate the AuAg nanocomposites, through the reduction of tannic acid (TNA). The bioactivity of the nanocomposites was investigated inS. aureusbiofilm-exposed human osteoblast cells (hFOB1.19). The current synthesis method is a simple, low-cost, eco-friendly, and green chemistry approach. Our results showed that the AuAg nanocomposites were biocompatible with low cell toxicity, and did not induce cell apoptosis nor necrosis in hFOB1.19 cells. Moreover, AuAg nanocomposites could effectively inhibited the accumulation of reactive oxygen species (ROS) in mitochondria and in rest of cellular compartments after exposing to bacterial biofilm (by reducing 0.78, 0.77-fold in the cell and mitochondria, respectively). AuAg nanocomposites also suppressed ROS-triggered inflammatory protein expression via MAPKs and Akt pathways. The current data suggest that AuAg nanocomposites have the potential to be a good therapeutic agent in treating inflammation in bacteria-infected bone diseases.

Identification of N-(3-(methyl(3-(orotic amido)propyl)amino)propyl) oleanolamide as a novel topoisomerase I catalytic inhibitor by rational design, molecular dynamics simulation, and biological evaluation.

DNA topoisomerase I (TOP1) catalytic inhibitors are a promising class of antitumor agents. Oleanolic acid derivatives are potential TOP1 catalytic inhibitors. However, their inhibitory activity still needs to be enhanced, and the stability and hotspot residue sites of their interaction with TOP1 remain to be elucidated. Herein, a novel oleanolic acid derivative, OA4 (N-(3-(methyl(3-(orotic amido)propyl)amino)propyl)oleanolamide), was identified by rational design. Subsequently, molecular dynamics simulations were performed to explore the stability and conformational dynamics of the TOP1-OA4 complex. The molecular mechanics/generalized Born surface area method calculated the binding free energy and predicted Arg488, Ile535, and His632 to be hotspot residues. Biological experiments verified that OA4 is a nonintercalative TOP1 catalytic inhibitor. OA4 exhibits better proliferation inhibitory activity against tumor cells than normal cells. Furthermore, OA4 can induce apoptosis and effectively suppress the proliferation and migration of cancer cells. This work provides new insights for the development of novel TOP1 catalytic inhibitors.

Relationship between childhood maltreatment and cognitive function in medication-free patients with major depressive disorder.

This study aimed to elucidate the contribution of childhood maltreatment (CM) and the disease of major depressive disorder (MDD) on cognitive function in medication-free patients in a current depressive episode, and to examine the effect of CM on the improvement of cognitive function after treatment with antidepressants. One hundred and fifty-three unmedicated patients with MDD and 142 healthy controls (HCs) underwent clinical interviews. CM assessment was performed using the Childhood Trauma Questionnaire (CTQ), and a battery of comprehensive neurocognitive tests was used to assess the participants' executive function, processing speed, attention, and memory. After 6 months of treatment with antidepressants, the neurocognitive tests were reperformed in patients with MDD and HCs. There was a significant main effect of MDD on all four cognitive domains, while the main effect of CM was only significant on memory. No significant interactive effect was found between MDD and CM on any of the cognitive domains. In the MDD group, higher CTQ total score was predictive of poorer memory performance. After treatment, significant main effects of treatment and MDD were found on all four cognitive domains in remitted patients with MDD. No significant main effect of CM or three-way interaction effect of treatment × MDD × CM was found on any of the cognitive domains. The disease of MDD contributed to impairments in all four cognitive domains. CM independently contributed to memory impairment in patients in a current depressive episode, with higher severity of CM predictive of poorer memory performance.

Impact of childhood maltreatment on adult resilience.

BACKGROUND: Previous studies suggested that childhood maltreatment is associated with poor health outcomes. While not everyone who experiences abuse as a child goes on to experience poor mental health, some traumatized people are grown to be more resilient than others. Few studies have examined the association between childhood maltreatment and adult resilience. This study aimed to determine different relationships between specific types and features of childhood maltreatment with adult resilience among Chinese with Major Depressive Disorder (MDD) and healthy controls (HCs). METHODS: A total of 101 patients with MDD and 116 participants in the healthy control (HC) group from Zhumadian Psychiatric Hospital and its nearby communities were included in this analysis. Childhood maltreatment was assessed retrospectively using Childhood Trauma Questionnaire (CTQ). Adults' resilience was assessed by the Connor-Davidson Resilience Scale (CD-RISC). Generalized linear models were applied between childhood maltreatment (specific types and features) and resilience adjusting for covariates. RESULTS: The total score of CD-RISC and factor scores of strength, optimism, and tenacity in the HC group were higher than those in the MDD group. CTQ total score had a negative association with optimism score among participants in MDD (ß=-0.087, P < 0.001) and HC (ß=-0.074, P = 0.023) groups. Higher emotional neglect (EN) score (ß=-0.169, P = 0.001) and physical neglect (PN) score (ß=-0.153, P = 0.043) were related to a worse optimism score in MDD group. Emotional abuse (EA) score was associated with a worse tenacity score (ß=-0.674, P = 0.031) in MDD group. For participants in HC group, higher EN and PN scores were related to worse resilience scores (tenacity, strength, and optimism). CONCLUSIONS: Patients with MDD showed lower optimism than HCs. Childhood maltreatment, especially childhood negect, independently contributed to optimism, with more severe childhood maltreatment predictive of worse performance of optimism. EA in childhood was also linked to worse tenacity in adult patients with MDD.

The relationship between personality traits and dysfunctional attitudes in individuals with or without major depressive disorder: a case control study.

BACKGROUND: Dysfunctional attitudes, which are characterized by distorted self-cognitions, were considered to be linked to personality traits. It was found that certain personality traits may predict dysfunctional attitudes in patients with major depressive disorder (MDD). Nonetheless, the relationship between personality traits and dysfunctional attitudes remains under-researched. AIMS: The aim of this study is to examine the relationship between specific domains of Sixteen Personality Factor (16PF) and dysfunctional attitudes in Chinese participants with or without MDD. In addition, the present study explores the associations between 16PF and eight subtypes of dysfunctional attitudes, based on the proposed eight-factor structure of the Chinese version of the Dysfunctional Attitude Scale-Form A (C-DAS-A). METHODS: One hundred and sixty-eight participants with MDD and 130 healthy participants were included in the study (Trial Registration Number: ChiCTR1800014591). Personality was assessed using the 16PF Questionnaire. Dysfunctional attitudes were measured through the C-DAS-A. RESULTS: The 16PF dimensions associated with dysfunctional attitudes and the eight subtypes were mainly concentrated in the four anxiety facets including factors C, L, O, and Q4, in both MDD and HC groups. There were significant differences in the 16 PF dimensions that would explain dysfunctional attitudes between the two groups, which were as follows: factors C, G, and O in the MDD group, and factors L and Q4 in the HC group. CONCLUSIONS: Personality traits, especially the anxiety-related personality traits, were distinctly associated with the development of dysfunctional attitudes in people with or without MDD.

Theranostic doxorubicin encapsulated FeAu alloy@metal-organic framework nanostructures enable magnetic hyperthermia and medical imaging in oral carcinoma.

Metal-organic frameworks (MOFs) have emerged as attractive candidates in cancer theranostics due to their ability to envelop magnetic nanoparticles, resulting in reduced cytotoxicity and high porosity, enabling chemodrug encapsulation. Here, FeAu alloy nanoparticles (FeAu NPs) are synthesized and coated with MIL-100(Fe) MOFs to fabricate FeAu@MOF nanostructures. We encapsulated Doxorubicin within the nanostructures and evaluated the suitability of this platform for medical imaging and cancer theranostics. FeAu@MOF nanostructures (FeAu@MIL-100(Fe)) exhibited superparamagnetism, magnetic hyperthermia behavior and displayed DOX encapsulation and release efficiency of 69.95 % and 97.19 %, respectively, when stimulated with alternating magnetic field (AMF). In-vitro experiments showed that AMF-induced hyperthermia resulted in 90 % HSC-3 oral squamous carcinoma cell death, indicating application in cancer theranostics. Finally, in an in-vivo mouse model, FeAu@MOF nanostructures improved image contrast, reduced tumor volume by 30-fold and tumor weight by 10-fold, which translated to enhancement in cumulative survival, highlighting the prospect of this platform for oral cancer treatment.

Fully automatic tumor segmentation of breast ultrasound images with deep learning.

BACKGROUND: Breast ultrasound (BUS) imaging is one of the most prevalent approaches for the detection of breast cancers. Tumor segmentation of BUS images can facilitate doctors in localizing tumors and is a necessary step for computer-aided diagnosis systems. While the majority of clinical BUS scans are normal ones without tumors, segmentation approaches such as U-Net often predict mass regions for these images. Such false-positive problem becomes serious if a fully automatic artificial intelligence system is used for routine screening. METHODS: In this study, we proposed a novel model which is more suitable for routine BUS screening. The model contains a classification branch that determines whether the image is normal or with tumors, and a segmentation branch that outlines tumors. Two branches share the same encoder network. We also built a new dataset that contains 1600 BUS images from 625 patients for training and a testing dataset with 130 images from 120 patients for testing. The dataset is the largest one with pixel-wise masks manually segmented by experienced radiologists. Our code is available at https://github.com/szhangNJU/BUS_segmentation. RESULTS: The area under the receiver operating characteristic curve (AUC) for classifying images into normal/abnormal categories was 0.991. The dice similarity coefficient (DSC) for segmentation of mass regions was 0.898, better than the state-of-the-art models. Testing on an external dataset gave a similar performance, demonstrating a good transferability of our model. Moreover, we simulated the use of the model in actual clinic practice by processing videos recorded during BUS scans; the model gave very low false-positive predictions on normal images without sacrificing sensitivities for images with tumors. CONCLUSIONS: Our model achieved better segmentation performance than the state-of-the-art models and showed a good transferability on an external test set. The proposed deep learning architecture holds potential for use in fully automatic BUS health screening.

Effects of HMW-GSs at Glu-B1 locus on starch-protein interaction and starch digestibility during thermomechanical processing of wheat dough.

BACKGROUND: The composition of glutenin protein significantly affects protein-starch interactions and starch digestion characteristics in wheat dough matrices. To elucidate the effects of high molecular weight glutenin subunits at the Glu-B1 locus on dough processing quality, the detailed structural changes of protein, starch, and their complexes were compared in Mixolab dough samples of two near isogenic lines 7 + 8 and 7 + 9. RESULTS: The results showed that the degree of protein aggregation increased continuously during dough processing, as did the destruction and rearrangement of the gluten network. Compared to 7 + 8, the stronger and more stable protein network formed in 7 + 9 dough induced intensive interactions between protein and starch, primarily through hydrogen bonds and isomeric glycosidic bonds. In 7 + 9 dough, the more compact and extensive protein-starch network significantly inhibited starch gelatinization during dough pasting, while during the dough cooling stage [from C4 (82.8 °C) to C5 (52.8 °C)], more protein-starch complexes composed of monomeric proteins and short-chain starch were generated, which remarkably inhibited starch retrogradation. All protein-starch interactions in the 7 + 9 dough improved the starch digestion resistance, as reflected by the high content of resistant starch. CONCLUSION: The more extensive and intensive protein-starch interactions in the 7 + 9 dough inhibited the gelatinization and enzymatic hydrolysis of starch, thereby producing more slowly digestible starch and resistant starch. These findings demonstrate the feasibility of optimizing the texture and digestibility of wheat-based food products by regulating the behavior and interactions of proteins and starch during dough processing. © 2022 Society of Chemical Industry.

Effect of Anti-CD4 Antibody UB-421 on HIV-1 Rebound after Treatment Interruption.

BACKGROUND: Administration of a single broadly neutralizing human immunodeficiency virus (HIV)-specific antibody to HIV-infected persons leads to the development of antibody-resistant virus in the absence of antiretroviral therapy (ART). It is possible that monotherapy with UB-421, an antibody that blocks the virus-binding site on human CD4+ T cells, could induce sustained virologic suppression without induction of resistance in HIV-infected persons after analytic treatment interruption. METHODS: We conducted a nonrandomized, open-label, phase 2 clinical study evaluating the safety, pharmacokinetics, and antiviral activity of UB-421 monotherapy in HIV-infected persons undergoing analytic treatment interruption. All the participants had undetectable plasma viremia (<20 copies of HIV RNA per milliliter) at the screening visit. After discontinuation of ART, participants received eight intravenous infusions of UB-421, at a dose of either 10 mg per kilogram of body weight every week (Cohort 1) or 25 mg per kilogram every 2 weeks (Cohort 2). The primary outcome was the time to viral rebound (≥400 copies per milliliter). RESULTS: A total of 29 participants were enrolled, 14 in Cohort 1 and 15 in Cohort 2. Administration of UB-421 maintained virologic suppression (<20 copies per milliliter) in all the participants (94.5% of measurements at study visits 2 through 9) during analytic treatment interruption, with intermittent viral blips (range, 21 to 142 copies per milliliter) observed in 8 participants (28%). No study participants had plasma viral rebound to more than 400 copies per milliliter. CD4+ T-cell counts remained stable throughout the duration of the study. Rash, mostly of grade 1, was a common and transient adverse event; one participant discontinued the study drug owing to a rash. A decrease in the population of CD4+ regulatory T cells was observed during UB-421 monotherapy. CONCLUSIONS: UB-421 maintained virologic suppression (during the 8 to 16 weeks of study) in participants in the absence of ART. One participant discontinued therapy owing to a rash. (Funded by United Biomedical and others; ClinicalTrials.gov number, NCT02369146.).

Iron oxide@chlorophyll clustered nanoparticles eliminate bladder cancer by photodynamic immunotherapy-initiated ferroptosis and immunostimulation.

The escape of bladder cancer from immunosurveillance causes monotherapy to exhibit poor efficacy; therefore, designing a multifunctional nanoparticle that boosts programmed cell death and immunoactivation has potential as a treatment strategy. Herein, we developed a facile one-pot coprecipitation reaction to fabricate cluster-structured nanoparticles (CNPs) assembled from Fe3O4 and iron chlorophyll (Chl/Fe) photosensitizers. This nanoassembled CNP, as a multifunctional theranostic agent, could perform red-NIR fluorescence and change the redox balance by the photoinduction of reactive oxygen species (ROS) and attenuate iron-mediated lipid peroxidation by the induction of a Fenton-like reaction. The intravesical instillation of Fe3O4@Chl/Fe CNPs modified with 4-carboxyphenylboronic acid (CPBA) may target the BC wall through glycoproteins in the BC cavity, allowing local killing of cancer cells by photodynamic therapy (PDT)-induced singlet oxygen and causing chemodynamic therapy (CDT)-mediated ferroptosis. An interesting possibility is reprogramming of the tumor microenvironment from immunosuppressive to immunostimulatory after PDT-CDT treatment, which was demonstrated by the reduction of PD-L1 (lower "off" signal to the effector immune cells), IDO-1, TGF-ß, and M2-like macrophages and the induction of CD8+ T cells on BC sections. Moreover, the intravesical instillation of Fe3O4@Chl/Fe CNPs may enhance the large-area distribution on the BC wall, improving antitumor efficacy and increasing survival rates from 0 to 91.7%. Our theranostic CNPs not only demonstrated combined PDT-CDT-induced cytotoxicity, ROS production, and ferroptosis to facilitate treatment efficacy but also opened up new horizons for eliminating the immunosuppressive effect by simultaneous PDT-CDT.

Effects of Sex and Obesity on LEP Variant and Leptin Level Associations in Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD), for which obesity and genetics are known risk factors, is a chronic process that alters the structure and function of the intervertebral discs (IVD). Circulating leptin is positively correlated with body weight and is often measured to elucidate the pathogenesis of IVD degeneration. In this study, we examined the associations of LEP single nucleotide polymorphisms (SNPs) genetic and environmental effects with IVDD. A total of 303 Taiwanese patients with IVDD (mean age, 58.6 ± 12.7 years) undergoing cervical discectomy for neck pain or lumbar discectomy for back pain were enrolled. Commercially available enzyme-linked immunosorbent assay (ELISA) kits measured the circulating plasma leptin levels. TaqMan SNP genotyping assays genotyped the LEP SNPs rs2167270 and rs7799039. Leptin levels were significantly increased in obese individuals (p < 0.001) and non-obese or obese women (p < 0.001). In the dominant model, recoded minor alleles of rs2167270 and rs7799039 were associated with higher leptin levels in all individuals (p = 0.011, p = 0.012). Further, the association between these LEP SNPs and leptin levels was significant only in obese women (p = 0.025 and p = 0.008, respectively). There was an interaction effect between sex and obesity, particularly among obese women (interaction p = 0.04 and 0.02, respectively). Our findings demonstrate that these SNPs have sex-specific associations with BMI in IVDD patients, and that obesity and sex, particularly among obese women, may modify the LEP transcription effect.

Identification of COVID-19 B-cell epitopes with phage-displayed peptide library.

BACKGROUND: Coronavirus disease 19 (COVID-19) first appeared in the city of Wuhan, in the Hubei province of China. Since its emergence, the COVID-19-causing virus, SARS-CoV-2, has been rapidly transmitted around the globe, overwhelming the medical care systems in many countries and leading to more than 3.3 million deaths. Identification of immunological epitopes on the virus would be highly useful for the development of diagnostic tools and vaccines that will be critical to limiting further spread of COVID-19. METHODS: To find disease-specific B-cell epitopes that correspond to or mimic natural epitopes, we used phage display technology to determine the targets of specific antibodies present in the sera of immune-responsive COVID-19 patients. Enzyme-linked immunosorbent assays were further applied to assess competitive antibody binding and serological detection. VaxiJen, BepiPred-2.0 and DiscoTope 2.0 were utilized for B-cell epitope prediction. PyMOL was used for protein structural analysis. RESULTS: 36 enriched peptides were identified by biopanning with antibodies from two COVID-19 patients; the peptides 4 motifs with consensus residues corresponding to two potential B-cell epitopes on SARS-CoV-2 viral proteins. The putative epitopes and hit peptides were then synthesized for validation by competitive antibody binding and serological detection. CONCLUSIONS: The identified B-cell epitopes on SARS-CoV-2 may aid investigations into COVID-19 pathogenesis and facilitate the development of epitope-based serological diagnostics and vaccines.

Loss of Wnt16 Leads to Skeletal Deformities and Downregulation of Bone Developmental Pathway in Zebrafish.

Wingless-type MMTV integration site family, member 16 (wnt16), is a wnt ligand that participates in the regulation of vertebrate skeletal development. Studies have shown that wnt16 can regulate bone metabolism, but its molecular mechanism remains largely undefined. We obtained the wnt16-/- zebrafish model using the CRISPR-Cas9-mediated gene knockout screen with 11 bp deletion in wnt16, which led to the premature termination of amino acid translation and significantly reduced wnt16 expression, thus obtaining the wnt16-/- zebrafish model. The expression of wnt16 in bone-related parts was detected via in situ hybridization. The head, spine, and tail exhibited significant deformities, and the bone mineral density and trabecular bone decreased in wnt16-/- using light microscopy and micro-CT analysis. RNA sequencing was performed to explore the differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the down-regulated DEGs are mainly concentrated in mTOR, FoxO, and VEGF pathways. Protein-protein interaction (PPI) network analysis was performed with the detected DEGs. Eight down-regulated DEGs including akt1, bnip4, ptena, vegfaa, twsg1b, prkab1a, prkab1b, and pla2g4f.2 were validated by qRT-PCR and the results were consistent with the RNA-seq data. Overall, our work provides key insights into the influence of wnt16 gene on skeletal development.

Complete genome analysis of a virulent Vibrio scophthalmi strain VSc190401 isolated from diseased marine fish half-smooth tongue sole, Cynoglossus semilaevis.

BACKGROUND: Vibrio scophthalmi is an opportunistic bacterial pathogen, which is widely distributed in the marine environment. Earlier studies have suggested that it is a normal microorganism in the turbot gut. However, recent studies have confirmed that this bacterial strain can cause diseases in many different marine animals. Therefore, it is necessary to investigate its whole genome for better understanding its physiological and pathogenic mechanisms. RESULTS: In the present study, we obtained a pathogenic strain of V. scophthalmi from diseased half-smooth tongue sole (Cynoglossus semilaevis) and sequenced its whole genome. Its genome contained two circular chromosomes and two plasmids with a total size of 3,541,838 bp, which harbored 3185 coding genes. Among these genes, 2648, 2298, and 1915 genes could be found through annotation information in COG, Blast2GO, and KEGG databases, respectively. Moreover, 10 genomic islands were predicted to exist in the chromosome I through IslandViewer online system. Comparison analysis in VFDB and PHI databases showed that this strain had 334 potential virulence-related genes and 518 pathogen-host interaction-related genes. Although it contained genes related to four secretion systems of T1SS, T2SS, T4SS, and T6SS, there was only one complete T2SS secretion system. Based on CARD database blast results, 180 drug resistance genes belonging to 27 antibiotic resistance categories were found in the whole genome of such strain. However, there were many differences between the phenotype and genotype of drug resistance. CONCLUSIONS: Based on the whole genome analysis, the pathogenic V. scophthalmi strain contained many types of genes related to pathogenicity and drug resistance. Moreover, it showed inconsistency between phenotype and genotype on drug resistance. These results suggested that the physiological mechanism seemed to be complex.

How intrahepatic cholestasis affects liver stiffness in patients with chronic hepatitis B: a study of 1197 patients with liver biopsy.

OBJECTIVES: To evaluate the impact of intrahepatic cholestasis on liver fibrosis staging using liver stiffness measurements (LSM). METHODS: Between July 2011 and September 2016, a total of 1197 patients with chronic hepatitis B (CHB) infection were enrolled to collect clinical, biological, 2D shear wave elastography (SWE), and histological (METAVIR scoring system) data. LSM was compared in patients with normal total bilirubin (TB) versus abnormal TB for each group of fibrosis stage, alanine aminotransferase (ALT) levels, and inflammation grade. Logistic regression and ROC analyses were performed to assess the benefit of adding TB and to LSM for fibrosis staging. RESULTS: Nine hundred and seventy-three patients were analyzed. Within the same fibrosis stage, LSMs showed significantly higher value in patients with abnormal TB than those with normal TB. Increased LSM for abnormal TB was generally found within different sub-groups of patients (≤ F2 or ≥ F3; ALT < 2 × upper limit of normal (ULN) or ALT ≥ 2 × ULN; METAVIR activity grade ≤ 1 or ≥ 2). Patients with abnormal TB level showed higher optimal cutoff values: 10.46 kPa for ≥ F2, 10.94 kPa for ≥ F3, and 15.88 kPa for F4, than those with normal TB (7.62 kPa, 8.26 kPa, and 11.01 kPa, respectively). LSM assessed fibrosis stage (≥ F2, ≥ F3, F4) showed higher false positive rate in patients with abnormal TB level (44.6%, 45.1%, 39.6%) than those with normal TB (20.7%, 17.1%, 14.4%). However, the area under the ROC curve did not change appreciably when adding TB to LSM for fibrosis stage. CONCLUSION: Intrahepatic cholestasis showed slight effect on LSM in patients with CHB, also leading to overestimation of liver fibrosis stages. But adding TB level to LSM did not improve the overall diagnostic performance of liver fibrosis stage. KEY POINTS: • Intrahepatic cholestasis showed slight effect on liver stiffness measurements (LSMs) in chronic HBV patients. • Patients with abnormal total bilirubin (TB) level showed higher optimal cutoff values and false positive rate. • When taking into account intrahepatic cholestasis, the diagnostic performance of LSM for liver fibrosis staging in patients with chronic HBV infection will not improve.

The Current Understanding of Autophagy in Nanomaterial Toxicity and Its Implementation in Safety Assessment-Related Alternative Testing Strategies.

Nanotechnology has rapidly promoted the development of a new generation of industrial and commercial products; however, it has also raised some concerns about human health and safety. To evaluate the toxicity of the great diversity of nanomaterials (NMs) in the traditional manner, a tremendous number of safety assessments and a very large number of animals would be required. For this reason, it is necessary to consider the use of alternative testing strategies or methods that reduce, refine, or replace (3Rs) the use of animals for assessing the toxicity of NMs. Autophagy is considered an early indicator of NM interactions with cells and has been recently recognized as an important form of cell death in nanoparticle-induced toxicity. Impairment of autophagy is related to the accelerated pathogenesis of diseases. By using mechanism-based high-throughput screening in vitro, we can predict the NMs that may lead to the generation of disease outcomes in vivo. Thus, a tiered testing strategy is suggested that includes a set of standardized assays in relevant human cell lines followed by critical validation studies carried out in animals or whole organism models such as C. elegans (Caenorhabditis elegans), zebrafish (Danio rerio), and Drosophila (Drosophila melanogaster)for improved screening of NM safety. A thorough understanding of the mechanisms by which NMs perturb biological systems, including autophagy induction, is critical for a more comprehensive elucidation of nanotoxicity. A more profound understanding of toxicity mechanisms will also facilitate the development of prevention and intervention policies against adverse outcomes induced by NMs. The development of a tiered testing strategy for NM hazard assessment not only promotes a more widespread adoption of non-rodent or 3R principles but also makes nanotoxicology testing more ethical, relevant, and cost- and time-efficient.

Reseach progress in neuroinflammation mechanism in depression. / æŠ‘éƒç—‡ç¥žç»ç‚Žç—‡æœºåˆ¶çš„ç ”ç©¶è¿›å±•.

Neuroinflammation is the innate immune response of the central nervous system, characterized by microglia activation, which can be accompanied with activation of astrocytes and increased levels of inflammatory factors and chemokines.Recent studies indicate that depressive patients have characteristic changes in neuroinflammation, mainly characterized by activation of microglia in the relevant brain regions. At present, the clinical results of positron emission tomography have found that the expression of neuroinflammatory imaging markers in the brain of patients with depression is increased.

Off-Resonance SERS Nanoprobe-Targeted Screen of Biomarkers for Antigens Recognition of Bladder Normal and Aggressive Cancer Cells.

The discovery of different binding receptors to allow rapid and high-sensitivity detection via a noninvasive urine test has become the goal for urothelial carcinoma (UC) diagnosis and surveillance. In this study, we developed a new screening membrane receptor platform for bladder cancer cells by integrating surface-enhanced Raman spectroscopy (SERS) with 4-aminothiophenol (4-ATP)-modified AuAg nanohollows upon NIR laser excitation. AuAg nanohollows have an absorption band at ∼630 nm, and slightly off-resonance 785 nm laser excitation is used for minimal photothermal effect. Using the same carbodiimide cross-linker chemistry to conjugate anti-EGFR, transferrin (TF), 4-carboxyphenylboronic acid (CPBA), folic acid (FA), and hyaluronic acid (HA) molecules, by screening the 4-ATP SERS signals intensity, we demonstrated that the targeting efficiency with the cost-effective CPBA molecule is comparable with the conjugation of anti-EGFR antibody to aggressive T24 cancer cells (high-grade), while weak intensity 4-ATP SERS responses to targets were obtained by grade-I RT4 bladder cancer cells, NIH/3T3 fibroblast cells, and SV-HUC1 bladder normal cells. This SERS nanoprobe platform makes primary bladder carcinoma screening from in vitro to ex vivo more straightforward. Our demonstration offers exciting potential for SERS screening of specific receptors on cancer cells of different grades and facilitates new opportunities ranging from surface engineering of SERS material tags to SERS imaging-guided and targeted phototherapy of cancer cells by controlling the laser powers.